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The Influence of Syphilis in Cancer of the Cervix Uteri Warren G. Harding, 2nd, M.D., F.R.C.S. (From the Hornsby District Hospital and Department o~ Pathology, University of Sydney, Sydney, Australia) (Received for publication August II, I94~) The data available do not give reliable information on the treatment given for syphilis in the 7 cases which had been diagnosed prior to the diagnosis of cancer. Three of them had rcceived known efficient treatment for a period of 4 and 5 years. Unfortunately the question of leukoplakia and condylomas preceding the development of carcinoma in this series cannot be answered from our records. The problem of the influence of syphilis upon the neoplastic process in general has not been solved. Some investigators, on the one hand, have ascribed to syphilis an etiological role. Others deny any relationship betwcen the two diseases. The consensus of opinion (2), however, is that an inter-relation exists between the two in the case of carcinoma of the buccal cavity, though the mode of interaction is not known. In addition to a causative role is the influence that syphilis may exert on thc clinical course of a tumor through the personal equation involved or through some alteration in the pathology of the disease. Regardless of the lack of objective data bearing upon this subject there is a widespread impression among radiologists that when cancer appears in a syphilitic patient the prognosis is very much less favorable than in the absence of a spirochetal infection. In a recent article Rosh (5) has summarized the opinion of radiologists as follows: "We may state at this point, that patients who had a previous syphilitic infection show a tendency to earlier recurrence. It is our impression that this applies to the untreated syphilitic as well as to the treated ones, particularly in the younger age groups." To a lesser degree the opinion is held among pathologists and clinicians that cancer is more highly malignant in the syphilitic patient. Black ( i ) concluded that "A final possibility is that in leaving syphilis untreated during the treatment of cancer the prognosis may be worsened, but I do not know of any evidence to this effect." Recently Schrader (6) reported 47 cases of cervical cancer occurring in women with positive serology for syphilis, a group representing approximately 4 per cent of his total series. In this group of 47 only 7 had had adequate antiluetic therapy. He concluded that syphilitic women, with or without adequate antisyphilitic therapy, respond poorly to radiation treatment and suggested that radiation morbidity from such causes as bladder and rectal distress and anemia is greater than in those free from syphilis. The following investigation was undertaken to study this problem, using data obtained at the time a positive diagnosis of cervical uterine cancer was made. The symptoms, physical findings, and histopathology have all been tabulated and considered. No attempt has been made to include the results of treatment as this aspect will be dealt with in full at a later date. CLINICAL MATERIAL The data were derived from the records of 227 consecutive cases of epithelioma of the cervix uteri seen at the Los Angeles General Hospital and the Hornsby District Hospital in Sydney, Australia. The only factor of selection operating on the total series consisted of the restriction that the patients be unable to pay for treatment in private hands but this in no way affects the comparison within the group. A histopathologic confirmation of the diagnosis is available in each case, obtained either by biopsy or autopsy. Serologic examination of the blood was made in each patient and a positive complete fixation reaction was accepted as the criterion for the presence of syphilis. By this method 36 patients were considered to be syphilitic and 19I were classed as free from the disease. This gives a percentage incidence of I5.8. The total incidence of syphilis as indicated by routine blood tests in the hospital averages about 5 per cent but it cannot be used here for comparison as it is not corrected for the age and sex factors which obviously operate in a series of patients with cancer of the cervix uteri. The history, evaluation of the stage of involvement, and the pathologic grade of malignancy were made by independent observers and confirmed by the author. INFLUENCE ON AGE DISTRIBUTION It has been suggested that syphilis predisposes to the earlier appearance of cancer. The age distribution as regards extremes was the same in both groups varying from cases in the 3rd to the 8th decade. The incidence of the disease before 4 ~ years of age shows a slight weighting on the side of the luetic, though it is not statistically significant. The average age, however, for the series of syphilitic cases was 47 years, 59 Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1942 American Association for Cancer Research. 60 Cancer Research and for the nonsyphilitic 5i.~ years. The age distribution in periods of 5-year groups is graphically shown in Fig. ,. grade 2 tumors arc transitional cell growths between grades i and 3 in type. The results of grading the carcinomas in this series are shown graphically in Fig. 2. In both classes the highly malignant growths composed 2o pcr cent of the group. However, the grade i carcinomas comprised 35 per cent of the cases in the nonluetic group and only 2o per cent in the luetic group. This difference is not sufficient to be conclusive but docs give an indication of a tendency in this series. Further tabulation on a larger series will be undertaken at a later date. P\ zo ! \,, ',__ iI ~0 ~ , , ""~-----. INFLUENCE ON CLINICAL STAGE AT FIRST EXAMINATION Fro. I.--Graph showing the age distribution in 5-year periods in percentage of incidence. The (lotted line represents the syphilitic cases. At the time the positive diagnosis of cervical cancer was m a d e each case was classified according to the gO~0- ~0- r I 2O 0 m Gaa~l t 2. _I 3 o ~TaQt I 2 3 4 FIG. 2.--Diagram showing the percentage distribution of the pathologic grades of malignancy. The shaded area represents the syphilitic group. Fro. 3.--Diagram showing the percentage distribution according to stage of involvement when first seen clinically. The shaded area represents the syphilitic group. INFLUENCE ON GRADE OF MALIGNANCY The conception of assessing the degree of (malignant) activity present in a tumor is largely credited to Broders who worked out his system of four grades in epitheliomas. Depending upon the degree of anaplasia he classifies tumors in grade I when the cells resemble, to a large degree, the cells from which they have originated. If the majority of the cells are poorly differentiated and abnormal in morphology they are considered to indicate a rapidly growing tumor and this is called grade 4- Grades 2 and 3 are the intervening stages. In the case of cervical epitheliomas the grading as advocated by Martzloff (3, 4) considers only three grades, as the highly differentiated type known as grade i in Broders' system is rarely, if ever, seen. Fox our purpose we have used the Martzloff grading (3, 4). Grade i is composed of cells showing marked differentiation and with the presence of intercellular bridges. These may be termed the spinal cell type. T h e grade 3 cells are the most rapidly g r o w i n g cells and are typified as the spindle cell group. The extent of clinical involvement. The importance of the degree of invasion upon the question of operability or prognosis is so well recognized as to require no further comment. T h e stages are n u m b e r e d from i to 4, as follows: i. involvement limited to cervix; 2. limited to cervix and contiguous tissue (no fixation); 3. invasion of parametrium; 4. m a r k e d fixation in pelvis or distant metastases. In Fig. 3 the percentages in each stage of the luetic and nonluetic group are compared. It must be pointed out that 37 per cent of the nonsyphilitic group were found in stages i and 2 in contrast to only 22 per cent of the syphilitic group in the same stages. T h e importance of this difference in the prognosis of the disease is at once obvious. T h a t this difference is not due to the time element is seen from the fact that the period of time elapsing from the appearance of the first symptom to the time of seeking medical attention Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1942 American Association for Cancer Research. Harding--Syphilis and Cancer of the Cervix was 7.i m o n t h s in the syphilitic g r o u p and 8. 4 m o n t h s in the other. N o significance is attached to this difference as it is probably due to several long-neglected cases in the nonsyphilitic series w h o entered the hospital in a m o r i b u n d condition after approximately 4 years of symptoms. INFLUENCE OF MULTIPLE PREGNANCY It has been suggested that syphilis m a y exert an influence u p o n cancer of the cervix t h r o u g h the repeated injury to the cervix due to the m a n y miscarriages w h i c h so often accompany the disease. T h e present series of cases was studied in this aspect and it was f o u n d that the syphilitic patients had had an average of 4-9 pregnancies while the nonsyphilitic g r o u p had an average of 4.o. This could not be considered a reliable difference as one w o m a n in the f o r m e r g r o u p h a d had 3 8 miscarriages, a n u m b e r sufficient to m a k e the difference in two averages. T w e n t y one nonsyphilitic w o m e n of this series h a d never been pregnant, an incidence of approximately i2 per cent. This fact stresses the i m p o r t a n c e of a d e q u a t e local examinations in nulliparous w o m e n w h o c o m p l a i n of b l e e d i n g or discharge f r o m the vagina. SUMMARY I. Syphilitic w o m e n develop carcinoma at an average age of 47 years, as c o m p a r e d to 51 years in nonsyphilitic w o m e n in this series. 6I 2. A h i g h e r per cent of n o n s y p h i l i t i c cases is classified as grade I according to Martzloff's classifications. 3- T h e nonsyphilitic g r o u p s h o w e d lcss extensive i n v o l v e m e n t w h e n first e x a m i n e d t h a n the syphilitic group. 4- N o significant difference existed in the delay in o b t a i n i n g a d e q u a t e therapy. 5. T h e influence of multiple pregnancies w h e n the t w o groups are c o m p a r e d appears negligible. REFERENCES I. BLACK, I. I. M. Syphilis in Diagnosis and Prognosis of Cancer. Brit. M. J., 1:1313-1314. 1937. 2. Har~DiXC., W. G. The Importance of Syphilis in Neoplasia; Analytical Review. J. Canccr Research Com., Univ. Sydney, 7:137-146. I936. 3. MARTZLO~F,K. H. Carcinoma of the Cervix Uteri: A Pathological and Clinical Study with Particular Reference to the Relative Malignancy of the Neoplastic Process as Indicated by the Predominant Type of Cancer Cell. Bull. Johns Hopkins Hosp., 34:I41-149. 184-195. 1923. 4. MARTZLOFF,K. H. Cancer of the Cervix Uteri: Its Surgical Treatment and Criteria Essential to the Establishment of a Prognosis Following Operation. Surg., Gynec., & Obst., 42:183-2oo. I928. 5- Rosin, R. Factors Influencing the Prognosis in the Treatment of Carcinoma of the Cervix. Radiology, 35:I7-22. 194 o. 6. SCHRADER,E. Uber die Bedeutung der Lues ffir das Genitalkarzinom der Frau. Zentralbl. f. Gynak., 63:93o-934. I939. Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1942 American Association for Cancer Research. The Influence of Syphilis in Cancer of the Cervix Uteri Warren G. Harding Cancer Res 1942;2:59-61. Updated version E-mail alerts Reprints and Subscriptions Permissions Access the most recent version of this article at: http://cancerres.aacrjournals.org/content/2/1/59.citation Sign up to receive free email-alerts related to this article or journal. To order reprints of this article or to subscribe to the journal, contact the AACR Publications Department at [email protected]. To request permission to re-use all or part of this article, contact the AACR Publications Department at [email protected]. Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1942 American Association for Cancer Research.